Multiple myeloma is cancer of the plasma cells and currently remains incurable. We are interested in developing novel, mechanism-based combination approaches to improve therapy responses in myeloma. For preclinical validation studies, established cell lines, co-culture models, primary tumor cells of mouse or human origin, and mouse myeloma models (transgenic and cell line derived syngeneic, orthotopic model) are being used. Currently our lab is pursuing following lines of study:
- Oxidative stress-based therapies to increase myeloma cytotoxicity and re-sensitize drug-resistant disease. Bortezomib (BTZ, Velcade) is a reversible proteasome inhibitor that is effective in inducing myeloma remission, however resistance can arise. We published that BTZ acts as an effective radiation sensitizer in myeloma; combination of BTZ with skeleton-targeted radiation (153-Sm-EDTMP, Quadramet) increased myeloma cell cytotoxicity in vitro and in vivo (Blood 2006). Next, by combining dexamethasone with Quadramet, we attained synergistic killing of myeloma cells while protecting normal bone marrow hematopoiesis by selective increases in oxidative stress (Neoplasia 2010). We made the novel observation that IL-6 treatment increased myeloma cell resistance to oxidative stress inducing agents (i.e. ionizing radiation, dexamethasone) by up-regulating the NF-kB-dependent MnSOD expression (Biochemical Journal 2012). Notably, BTZ treatment increases oxidative stress in myeloma cells presumably by accumulation of misfolded proteins. To determine if redox-regulated pathways contribute to intrinsic or acquired BTZ resistance, we generated BTZ-resistant variants and also used myeloma cell lines with higher BTZ IC50 values. An up-regulation of CuZnSOD, GPx-1, and GSH correlated with BTZ resistance and decreased BTZ-mediated prooxidant production. Pharmacological inhibition of CuZnSOD with disulfiram (DSF, Antabuse) augmented BTZ cytotoxicity in the resistant cell lines (Redox Biology 2015). Our preliminary data indicates that an increase in glucose uptake and G6PD expression also associates with BTZ resistance. Ongoing studies are examining if targeting glycolytic and pentose phosphate pathway negatively impacts redox homeostasis and augments BTZ cytotoxicity in myeloma cells.
- Targeting altered redox status of clonogenic fraction for improving therapy responses in myeloma. Incurability of myeloma is partially attributed to the persistence of a distinct population of the stem cell-like cells. These clonotypic CD138− cells retain key stem cell properties, tumor-initiating potential, self-renewal, and resistance to chemotherapy. Also, the dominant CD138+ myeloma cells show plasticity potential via de-differentiation and gaining stem cell properties. Recent literature suggests that cancer stem cells frequently show fundamental differences in oxidative metabolism relative to normal stem cells. Ongoing studies are exploiting oxidative metabolism as the biochemical target to selectively induce cytotoxicity in the “putative” myeloma stem cells. In combination with BTZ, we are targeting prooxidant producing pathways and hydroperoxide removal pathways to eliminate these clonogenic myeloma cells.
Our preliminary data shows that culturing myeloma cells under hypoxia, which is a physiological feature of the bone marrow, results in “increased MM stemness” in vitro. It is established that miRs are differentially expressed in cancer but also altered by hypoxia. A miR expression array profiling showed that hypoxia induces a distinct expression profile of seven miRs that was common between four different myeloma cell lines. Ongoing studies are examining the role of these miRs in glycolytic metabolism and drug resistance in myeloma cells.
- Role of environmental carcinogens in tumor progression of plasma cell neoplasms. Epidemiological data shows an association between exposures to Agent Orange [containing traces of TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) carcinogen] with increased risk of monoclonal gammopathy of undetermined significance (MGUS). Our preliminary data show that in vitro treatment with TCDD or PCB126 (a potent PCB congener) results in increase oxidative stress and DNA damage in myeloma cells. In the double transgenic IL6Myc myeloma model, we are examining the role of oxidative stress, by dioxin-like carcinogens, as a determinant in myeloma progression and also utilizing small molecule antioxidants as an anti-carcinogenesis strategy.